Concurrent Mixed Phenotypic Acute Leukemia and T‐Lymphoblastic Lymphoma in an Adolescent Male

To the Editor; We describe the first documented case of a patient presenting concurrently with two molecularly distinct malignancies, mixed phenotypic acute leukemia (MPAL) (B/myeloid) and T-lymphoblastic lymphoma (T-LBL). MPAL is a rare, heterogeneous form of acute leukemia that exhibits both lymphoid and myeloid lineage features, whether within a single blast population (biphenotypic) or as distinct blast populations (bilineal). It accounts for less than 5% of all pediatric acute leukemias [1]. MPAL presents significant diagnostic and therapeutic challenges due to its phenotypic diversity and the lack of standardized treatment protocols. Furthermore, the simultaneous presentation of two distinct pediatric hematologic malignancies is exceedingly rare. A 15-year-old male presented with several weeks of progressively worsening facial swelling and dyspnea. Physical exam revealed absent right-sided breath sounds and supraclavicular lymphadenopathy without hepatosplenomegaly or testicular masses. Imaging showed a large anterior mediastinal mass compressing the superior vena cava and a large pleural effusion (Figure 1A). Complete blood count revealed pancytopenia (white blood cell count [WBC] 4 × 10⁹/L, absolute neutrophil count [ANC] 2.24 × 10⁹/L; hemoglobin 12.3 g/dL; platelets 17 × 10⁹/L) with rare circulating blasts, and an elevated lactate dehydrogenase (LDH) (684 IU/L). Supraclavicular lymph node biopsy (Figure 1C) and pleural fluid cytology confirmed T-lymphoblastic lymphoma (IHC/flow as seen in Figure 1E: CD3⁺, CD19−, MPO−, CD33⁺, TdT⁺; cytogenetics: 46, XY with t(9;11)(q13;q2); fusion analysis: NUP214::ABL1). FISH was negative for BCR-ABL1 and KMT2A rearrangements. Staging bone marrow aspirate revealed 72.3% blasts with a mixed B/myeloid immunophenotype (CD19⁺, CD79a⁺, PAX5⁺, CD22−, CD10−, CD3−, MPO⁺, TdT−) (Figure 1B,D). FISH demonstrated CDKN2A deletion and loss of the CRLF2 signal. Molecular studies identified FLT3-ITD and WT1 variants. These features fulfilled WHO criteria for MPAL (B/myeloid subtype), distinct from the concurrent T-lymphoblastic process. There was no central nervous system (CNS) involvement (CNS1). Germline testing with the Blueprint Hereditary Leukemia Panel showed no cancer predisposition mutations. The distinct cytogenetic, FISH, microarray, and molecular findings between the bone marrow and lymph node are outlined in Table 1. The patient was treated as per AALL1732, MPAL arm, with a four-drug induction (prednisone, vincristine, daunorubicin, asparaginase) [2]. Nelarabine was not included as it has not demonstrated improvement in outcomes for T-lymphoblastic lymphoma [3]. The end-of-induction evaluation showed no measurable bone marrow minimal residual disease (MRD) for B-cell (sensitivity <0.01%), and T-cell and myeloid disease (sensitivity <0.02%). The mediastinal mass decreased in size by the end of induction and resolved by the end of consolidation, with the PET scan showing no avidity. Treatment-related adverse events included mercaptopurine-associated hepatotoxicity, requiring allopurinol and ursodiol, which subsequently resolved, and vincristine-induced neuropathy, which improved after dose reduction. The patient is currently in his third cycle of maintenance therapy and remains in complete remission. Simultaneous occurrence of T-lymphoblastic lymphoma and a distinct acute leukemia in the marrow has been reported in isolated adult cases, often with shared clonality, suggesting a common progenitor [4]. However, in this pediatric patient, immunophenotypic and molecular findings support the presence of two independent neoplasms, each with separate lineage features and genetic alterations. CDK2NA deletion and loss of one signal for CRLF2 Negative for: KMT2A, IKZF1 deletion, BCR-ABL1, ETV6::RUNX1, AML panel Immunophenotyping remains the cornerstone of MPAL diagnosis, and should include myeloid and lymphoid markers with attention to exclusion of AML subtypes such as t(8;21) or complex karyotypes that may mimic MPAL [5]. Advanced genomic profiling has improved understanding of the heterogeneity of MPAL: mutations in FLT3-ITD, WT1, RUNX1, CDKN2A/B, and NOTCH1 are recurrent in pediatric series, while adult MPAL often shows complex cytogenetics, BCR-ABL1, or KMT2A rearrangements [6]. Notably, FLT3-ITD and WT1, found in our patient, have been described as enriched in pediatric MPAL and may represent potential therapeutic targets [6]. Though there is no current standard of care for treatment, ALL-directed chemotherapy remains first-line treatment for pediatric MPAL, given the association with superior long-term survival and lower relapse rates compared to AML-style therapy [7]. Published data largely consist of case series, but meta-analyses suggest chemotherapy with regimens designed for acute lymphoblastic leukemia (ALL) is associated with higher rates of complete remission after induction and equivalent overall survival [8]. A comparative study found that ALL-directed therapy elicited superior response rates compared to myeloid regimens (p = 0.001) [9]. Furthermore, a cohort and consensus study from the Children's Oncology Group in 2020 suggests that ALL-directed therapy without hematopoietic stem cell transplant (HSCT) is the preferred initial treatment for MPAL in pediatric patients [2]. Overall, this case underscores several key lessons. First, it emphasizes the importance of comprehensive immunophenotyping and molecular evaluation, as simultaneous hematologic malignancies may escape detection without these. Second, the genomic characterization plays an important role in potential targeted therapy options (e.g., FLT3-ITD) in the case of future relapse or refractory cases. Third, this case supports the use of ALL-directed regimens in B/myeloid MPAL and T-lymphoblastic lymphoma with good MRD response. This is the first known case of concurrent pediatric T-lymphoblastic lymphoma and MPAL of unrelated lineage. Awareness of such rare presentations is crucial for accurate diagnosis and therapeutic planning. Further case accumulation and studies are needed to guide management in these complex scenarios. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.